The liver is a dynamic organ that plays an important role in a variety of physiological processes. The complex functions of the liver include metabolism, storage, excretion, secretion of plasma proteins such as albumin and detoxification of harmful substances by enzymes of the cytochrome P-450 system. In addition, the usually quiescent liver is also capable of remarkable mitotic activities under certain circumstances. The major cell population of the liver is the parenchymal cells (PC), also known as hepatocytes. The liver also contains several other cell types such as endothelial cells, adipocytes, fibroblastic cells and Kupffer cells. The ability of liver cells to undergo rapid regeneration, when the liver is damaged or partially removed, makes the liver a potential source of stem cells.
It is currently believed that the liver has a stem cell and lineage system which has several parallels to the gut, skin and hemopoietic systems (Sigal et al., 1993 Amer. J. Physiol., 263:139-148). As such, there are progenitor cell populations in the liver of animals of all ages. These cells when isolated from the liver may serve as potential candidates for cell therapy.
The mammalian immune system plays a central role in protecting individuals from infectious agents and preventing tumor growth. However, the same immune system can produce undesirable effects such as the rejection of cell, tissue and organ transplants from unrelated donors. The immune system does not distinguish beneficial intruders, such as a transplanted tissue, from those that are harmful, and thus the immune system rejects transplanted tissues or organs. Rejection of transplanted organs is generally mediated by alloreactive T cells present in the host which recognize donor alloantigens or xenoantigens.
Immunologic tolerance is an actively induced unresponsiveness to a specific antigen as the result of antigen-induced functional inactivation or death of lymphocytes that are specific for that antigen. Antigens that induce such tolerance are termed “tolerogens,” so as to be distinguished from immunogens which are antigens that generate immune responses. One mechanism of B cell tolerance and failure to produce antibodies involves the interaction of antigens with specific B cells (the first step in B cell activation) in the absence of stimulation by helper T cells or other antigen presenting cells (the second step in B cell activation). Other mechanisms of B cell tolerance have been proposed. For example, B cells can become anergic due to a block in surface immunoglobulin-mediated signaling (“antigen-competition”), in the absence of T cells. Additionally, in the absence of co-stimulation by an antigen presenting cell, strong crosslinking of B cell surface immunoglobulins by an antigen can induce apoptotic death of normal, mature B cells, but may not induce apoptosis in B cells that produce autoimmune antibodies (Tsubata et al., 1994, Curr. Biol. 4:8-17).
T cell tolerance is achieved 1) in the thymus where thymocytes reactive for self-peptides are eliminated by clonal deletion (central tolerance), and 2) in the periphery by exposure to self-antigens under tolerogenic conditions (peripheral tolerance). Clonal deletion can also result from expression of cell death molecules on antigen presenting cells. Classic examples of cell death molecules are Fas ligand (FasL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL ligand), which ligate their receptors, Fas and DR4, respectively, on activated T cells, inducing apoptosis of the T cells. The interaction of CD27, a member of the TNFR superfamily, and the CD27-ligand (CD70) also induces T cell apoptosis.
The transplantation of cells, tissues, and organs between genetically disparate individuals invariably is associated with risk of graft rejection. Nearly all cells express products of the major histocompatibility complex, MHC class I molecules. Further, many cell types can be induced to express MHC class II molecules when exposed to inflammatory cytokines. Additional immunogenic molecules include those derived from minor histocompatibility antigens such as Y chromosome antigens recognized by female recipients. Rejection of allografts is mediated primarily by T cells of both the CD4 and CD8 subclasses (Rosenberg et al., 1992 Annu. Rev. Immunol. 10:333). Alloreactive CD4 T cells produce cytokines that exacerbate the cytolytic CD8 response to alloantigen. Within these subclasses, competing subpopulations of cells develop after antigen stimulation that are characterized by the cytokines they produce. Th1 cells, which produce IL-2 and IFN-γ, are primarily involved in allograft rejection (Mossmann et al., 1989 Annu. Rev. Immunol. 7:145). Th2 cells, which produce IL-4 and IL-10, can down-regulate Th1 responses through IL-10 (Fiorentino et al. 1989 J. Exp. Med. 170:2081). Indeed, much effort has been expended to divert undesirable Th1 responses toward the Th2 pathway. Undesirable alloreactive T cell responses in patients (allograft rejection, graft-versus-host disease) are typically treated with immunosuppressive drugs such as prednisone, azathioprine, and cyclosporine A. Unfortunately, these drugs generally need to be administered for the life of the patient and they have a multitude of dangerous side effects including generalized immunosuppression.
A major goal in organ transplantation is the permanent engraftment of the donor organ without inducing a graft rejection immune response generated by the recipient, while preserving the immunocompetence of the recipient against other foreign antigens. Typically, in order to prevent host rejection responses, nonspecific immunosuppressive agents such as cyclosporine, methotrexate, steroids and FK506 are used. These agents must be administered on a daily basis and if administration is stopped, graft rejection usually results. However, a major problem in using nonspecific immunosuppressive agents is that they function by suppressing all aspects of the immune response, thereby greatly increasing a recipient's susceptibility to infection and other diseases, including cancer.
Furthermore, despite the use of immunosuppressive agents, graft rejection still remains a major source of morbidity and mortality in human organ transplantation. Most human transplants fail within 10 years without permanent graft acceptance. Only 50% of heart transplants survive 5 years and 20% of kidney transplants survive 10 years. (Opelz et al., 1981, Lancet 1:1223).
It is currently believed that a successful transplantation is dependent on the prevention and/or reduction of an unwanted immune response by a host to a transplant mediated by immune effector cells to avert host rejection of donor tissue. Also advantageous for a successful transplantation is a method to eliminate or reduce an unwanted immune response by a donor tissue against a recipient tissue known as graft-versus-host disease. Thus, there is long-felt need for methods to suppress or otherwise prevent an unwanted immune response associated with transplantation of cells, tissues, and organs between genetically disparate individuals. The present invention meets this need.